The present invention relates to a pharmaceutical composition containing the p40 subunit of the cytokine interleukin-12 ("IL-12"). This composition is particularly suitable for use in the treatment of disorders which are associated with disregulation of the immune system.
Immune reactions are supported by different T-cell populations. Depending on the type of the immune reaction, T-cell help is provided either by Type 1 T-helper Cells (TH1) or by Type 2 T-helper cells (TH2). As far as is known to date, TH1 cells differ from TH2 cells, in particular, by producing cytokines.
Dunn et al., J. Immunol. 142:3847 (1989), demonstrated that TH1 clones produce gamma interferon (gamma-IFN), provided they are cultivated in the presence of accessory cells and IL-2. In addition, Germann et al., Eur. J. Immunol. 8:1857-1862 (1991), demonstrated that a soluble mediator is required for the synthesis of gamma-IFN by TH1 cells. It emerged from comparative investigations that the mediator designated TSF is identical to murine IL-12. Recently, Mengel et al., Eur. J. Immunol. 22:3173-3178 (1992), likewise described, in the supernatant of the activated murine B cell lymphoma line A-20, a soluble factor which stimulates gamma-IFN production in T-cells. The soluble factor described by Mengel et al. in the A-20 supernatant was compared functionally by Wolf et al., J. Immunol. 156:3074 (1991), with a so-called "human natural killer cell stimulatory factor" (NKSF) and was postulated to be the murine analog of human IL-12. It is known that IL-12 and NKSF, which may be identical, both stimulate gamma-IFN synthesis. The function of IL-12 or NKSF is not naturally limited to the stimulation of gamma-IFN production. Inter alia, IL-12 or NKSF also affects the function of (i) natural killer cells, so-called NK or LGL cells, (ii) IgE production and (iii) increases IL-12-induced proliferation of resting peripheral mononuclear cells.
It has been shown that IL-12 is composed of two subunits which are designated p35 and p40. Podlaski et al., Arch. Biochem. Biophys. 294:230-237 (1991). Murine IL-12 was found to have an almost identical structure. Schoenhaut et al., J. Immunol. 148:3433-3440 (1992). While the p40 subunit of IL-12 apparently does not possess any IL-12-specific bioactivity on its own, the p40 subunit is of considerable importance for the bioactivity of the complete IL-12 molecule. It has been speculated that p40 interacts directly with the cellular IL-12 receptor. There remains no evidence, however, of the particular role played by p40 in the immune function of IL-12.
It is well established in the literature that disregulation of cytokine production and cytokine effects may cause acute and chronic disorders of the immune system and their associated sequelae. In addition, influencing cytokine-mediated activities represents a potential therapeutic approach for many different cytokine-related disorders. Therefore, there is considerable interest in evaluating and affecting the function of IL-12 in mammalian subjects.